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Structure of 350-46-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 350-46-9 |
Formula : | C6H4FNO2 |
M.W : | 141.10 |
SMILES Code : | FC1=CC=C(C=C1)N(=O)=O |
MDL No. : | MFCD00007282 |
InChI Key : | WFQDTOYDVUWQMS-UHFFFAOYSA-N |
Pubchem ID : | 9590 |
GHS Pictogram: |
![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H227-H302+H312-H331-H373-H402 |
Precautionary Statements: | P210-P260-P264-P270-P271-P273-P280-P301+P312+P330-P302+P352+P312-P304+P340+P311-P314-P370+P378-P403+P233-P403+P235-P405-P501 |
Class: | 6.1 |
UN#: | 2811 |
Packing Group: | Ⅲ |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 35.22 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.39 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.8 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.68 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.2 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.51 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 0.837 mg/ml ; 0.00593 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.38 |
Solubility | 0.586 mg/ml ; 0.00416 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.51 |
Solubility | 0.437 mg/ml ; 0.0031 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.88 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.27 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In dimethyl sulfoxide; at 90℃; for 9h; | 4-Fluoronitrobenzene (323 mg, 2.3 mmol) was dissolved in DMSO (5 ml), potassium carbonate (475 mg, 3.5 mmol) and piperidine (460 mul, 4.6 mmol) were added, and the mixture was stirred at 90 C. for 9 hr. Then, water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with saturated aqueous NaCl. The organic layer was dried over Na2CO3, the solvent was evaporated to give compound Y197 (yield; 472 mg, 100%). Compound Y197 was dissolved in ethyl acetate (20 ml), Pd/C (186 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. Then, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (40:1)) to give compound Y222 (yield, quantitative, 394 mg). Compound Y491 (mentioned later) (80 mg, 0.18 mmol) was dissolved in dichloromethane (2 ml), compound Y222 (100 mg, 0.58 mmol) was added, and the mixture was stirred at room temperature for 5 hr. Then, the solvent was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (35:1)) to give the title compound (yield; 68 mg, 64%). 1H NMR (500 MHz, CDCl3) delta8.40 (s, 1H), 8.0 (d, 1H, J=8.0 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.52 (dd, 1H, J=8.0, 7.5 Hz), 6.92 (dd, 2H, J=9.0, 3.5 Hz), 6.77 (dd, 2H, J=9.0, 6.5 Hz), 5.33 (t, 1H, J=6.0 Hz), 4.07 (bs, 2H), 3.11-3.09 (m, 4H), 2.79-2.64 (m, 4H), 1.69-1.53 (m, 10H), 1.43 (s, 9H), 1.09-1.01 (m, 2H) 13C NMR (125 MHz, CDCl3) delta154.9, 141.6, 140.8, 131.4, 130.9, 129.8, 125.8, 125.7, 79.7, 77.4, 48.7, 36.6, 29.6, 28.6, 25.7, 24.2 HRMS (FAB-) m/z: [M-H]- calcd for C28H39N4O6S2, 591.2311. found, 591.2324 |
97% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 20h; | In a 250mL round-bottom flask equipped with a stirring bar, a mixture of 12.8g (0.15mol) of piperidine, 21.2g (0.15mol) of 4-fluoronitrobenzene, and 20.7g (0.15mol) of potassium carbonate (K2CO3) in 100mL of dimethyl sulfoxide (DMSO) was heated with stirring at 120C for 20h. After cooling, the mixture was poured into 400mL mixed solution of ethanol/water (1:1). The yellow crystals were collected by filtration with a yield of 30.0g (97%) and a melting point of 100-102C, measured by differential scanning calorimetry (DSC) at a scan rate of 10C/min. IR (KBr):1577, 1329cm-1 (-NO2 str.). 1H NMR (500MHz, DMSO-d6, delta, ppm): 8.02 (d, J=9.5Hz, 2H, He), 6.98 (d, J=9.5Hz, 2H, Hd), 3.49 (t, J=5.7Hz, 4H, Hc), 1.63 (m, 2H, Ha), 1.57 (m, 4H, Hb). 13C NMR (125MHz, DMSO-d6, delta, ppm): 154.5 (C4), 135.9 (C7), 125.8 (C6) 112.2 (C5), 47.5 (C3), 24.8 (C2), 23.8 (C1) |
75% | In dimethyl sulfoxide; at 80℃; for 20h; | Synthesis of 1-(4-Nitro-phenyl)-piperidine Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80 C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75%) of 1-(4-nitro-phenyl)-piperidine. |
54% | With potassium hydroxide; In dimethyl sulfoxide; at 80℃; for 16h; | General procedure: A mixture of 2-fluorobenzamide (1a, 69.5 mg, 0.5 mmol), MeOH (ca. 32.0 mg, 1.0 mmol), KOH (56.0 mg, 1.0 mmol) and DMSO (2.0 mL) in a 25 mL screw-capped thick-walled Pyrex tube was stirred at room temperature for 16 h, and then water (10 mL) was added to the reaction mixture with stirring, and the mixture was extracted with ethyl acetate three times (3 * 10 mL). The combined organic phases were dried over Na2SO4 overnight. The filtered solution was concentrated under reduced pressure, and the crude residue was purified by column chromatography on silica gel with the use of petroleum ether/ethyl acetate/trimethylamine (gradient mixture ratio from 6:1:0.05 to 2:1:0.05 in volume) to afford 2aa as a white solid in 80% yield (60.7 mg). |
46% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 5h;Inert atmosphere; | Step Reaction: 15.0g equipped with a mechanical stirring was added a 500mL three-necked flask (176mmol)Piperidine, 24.9g (176mmol) of fluoro nitrobenzene, 24.5g (176mmol) of potassium carbonate was added 250mLOf N, N- dimethylformamide as the solvent, with stirring, under nitrogen, the reaction at 110 5H, coldAfter cooling, ice water discharge, the crude product was washed with water three times, dried, and recrystallized from ethanol to give yellowPiperidin-4-nitrophenyl powder 16.7g, 46% yield; |
With sodium hydrogencarbonate; In N-methyl-acetamide; water; ethyl acetate; | (1) A solution of p-fluoronitrobenzene (31.8 ml) in dimethylformamide (200 ml) was ice-cooled and to this was added piperidine (60 ml) dropwise, followed by stirring with ice cooling for 2 hours. After the solvent was distilled off, the residual oily product was dissolved in ethyl acetate ester (200 ml), followed by washing in turn with aqueous saturated solution of sodium bicarbonate and water. Then, the solution was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from n-hexane to obtain N-(4-nitrophenyl)piperidine as yellow crystals (52.8 g). | |
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 48h; | A solution of 4-fluoronitrobenzene (1.41 g, 1.06 mL, O. OLMOL), N, N- diisopropylethylamine (1.1 equiv), and amine (1.1 equiv) IN N, N-DIMETHYLFORM- amide (8-10 mL) was heated at 100 C for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0 to 10% methanol-dichloromethane) to afford the nitroaniline | |
With N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 48h; | Method K; General method for the synthesis of 4-aminoanilines of type K.; Step 1:; A solution of 4-fluoronitrobenzene (1.41 g, 1.06 mL, O. Olmol), N, N- diisopropylethylamine (1.1 equiv), and amine (1.1 equiv) inN, N-dimethylform- amide (8-10 mL) was heated at 100 C for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0 to 10% methanol-dichloromethane) to afford the nitroaniline. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 40℃; | General procedure: Substituted amine (1.2 equiv) was added to a mixture of 4-fluoronitrobenzene (1 equiv) and K2CO3 (2.0 equiv) in DMF (7mL/g). The reaction mixture was stirred at 40C and followed by TLC. After completion of the reaction, the mixture was poured into stirring ice-water. The resulting precipitate was filtered and dried to obtain compounds 11 as a yellow solid. | |
With potassium carbonate; In dimethyl sulfoxide; at 0 - 80℃; for 8h; | General procedure: To a solution of 1-fluoro-4-nitrobenzene (5 g, 35.5 mmol) in DMSO(100 mL) was added K2CO3 (14.6 g, 106.4 mmol) at room temperature.And a solution of tert-butyl piperazine-1-carboxylate (3.5 g, 35.5 mmol)in DMSO (50 mL) was added dropwise to the mixture at 0 C. The reactionmixture was stirred at 80 C for 8 h. Water (500 mL) was added toquench the reaction. The precipitated solid was collected on a filter anddried under reduced pressure to give 1a (8.0 g, yield 73.5%) withoutfurther purification. MS m/z: 308.2 [M+H]+. The crude product wasdelivered directly to the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.61 g (68.7%) | In N-methyl-acetamide; water; | 1. 4-(1,1-dioxo-5-methyl-1,2,5-thiadiazolidine-2-yl)nitrobenzene To a solution of <strong>[67104-97-6]2-methyl-1,2,5-thiadiazolidine-1,1-dioxide</strong> (2.02 g, 14.8 mmol) in anhydrous dimethylformamide (30 ml) was added sodium hydride (60% dispersion in oil; 0.59 g) and the mixture was stirred at room temperature under nitrogen for 40 minutes. A solution of 1-fluoro-4-nitrobenzene (2.09 g, 14.8 mmol) in anhydrous dimethylformamide (15 ml) was added to the above solution and the mixture was refluxed for 1 hour. Water (200 ml) was added and products were extracted with ethyl acetate (2*150 ml), dried (MgSO4) and concentrated to an orange solid. Crystallisation from ethyl acetate (150 ml) afforded 2.61 g (68.7%) of the title compound as a pale orange solid; mp 155-163 C.; deltaH (250 MHz, DMSO-d6) 8.29 (2H, d, J=9.3 Hz, Ar--H), 7.34 (2H, d, J=9.3 Hz, Ar--H), 4.00 (2H, t, J=6.4 Hz, --CH2 --), 3.57 (2H, t, J=6.4 Hz, --CH2 --), 2.78 (3H, s, --CH3); m/z (EI) 257 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 73℃; for 18h; | General procedure: Step 1, 10.0 mmol of p-fluoronitrobenzene and compound A2 were dissolved in acetonitrile.The molar ratio of p-fluoronitrobenzene to compound A2 is C2,And adding potassium carbonate to the above solution,The molar ratio of potassium carbonate to p-fluoronitrobenzene is C3,The mixture was stirred at the temperature indicated by C1 for 18 h. After cooling to room temperature, The reaction solution was diluted with 40 mL of water and extracted with 3×40 mL of ethyl acetate.The organic phase was combined, washed with 2×50 mL of brine and dried over anhydrous sodium sulfate.Concentrated in vacuo and the residue obtained was purified by silica gel column chromatography(Eluent: n-hexane / ethyl acetate = 10:1) gave Compound A3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Step 1: Synthesis of 1-methyl-3-(4-nitrophenoxy)pyrrolidine To a solution of potassium tert-butoxide (1.43 g, 12.9 mmol) in THF (6 mL) was added 1-methylpyrrolidin-3-ol (645 mg, 6.39 mmol). The reaction mixture was stirred at room temperature for 1 h. Then 1-fluoro-4-nitrobenzene (900 mg, 6.39 mmol) was added to the above solution and stirred for another 2 h. After the removal of the volatile, the residual was dissolved in ethyl acetate (40 mL), and then washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (EA:PE=1:4) to give desired product as a yellow oil (626 mg, 44percent). | |
With sodium hydride; In 1-methyl-pyrrolidin-2-one; | Reference Example 33 4-Fluoronitrobenzene and 1-methylpyrrolidin-3-ol were allowed to undergo the reaction in 1-methylpyrrolidone in the presence of sodium hydride. The resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(1-methylpyrrolidin-3-yl)oxoaniline. F: 193. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Syntheses of Exemplified Compounds (see Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. | ||
Syntheses of Exemplified Compounds (See Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. | ||
SYNTHESES OF EXEMPLIFIED COMPOUNDS (See Tables for Compound Characterization) Entry 1: 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, <strong>[5369-19-7]3-tert-butylaniline</strong> was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea. Entry 2: 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; ammonia; In methanol; N,N-dimethyl-formamide; | Method 19 4-[(1-Methylpiperidin-2-yl)methoxy]nitrobenzene Sodium hydride (60percent dispersion in oil; 400 mg, 10.0 mmol) was added to a solution of 2-hydroxymethyl-1-methylpiperidine (1.29 g, 10.0 mmol) in DMF (20 ml) and the mixture was stirred for 2 hours. 4-Fluoronitrobenzene (1.4 g, 10.0 mmol) was added and the mixture was heated at 80° C. for 17 hours. The mixture was poured into water (100 ml) and extracted with ethyl acetate (2*100 ml). The extracts were washed with water (2*100 ml) and then extracted with 2M hydrochloric acid (2*50 ml). The combined acidic extracts were washed with ether (2*100 ml) and then basified by addition of 0.88 ammonia solution. The basified solution was extracted with ether (2*100 ml) and the extracts were washed with water (2*100 ml) and saturated sodium chloride (100 ml) and dried. Volatile material was removed by evaporation and a saturated solution of hydrogen chloride in methanol was added to the residue. Evaporation gave the hydrochloride salt of the product as an oil (2.4 g). NMR (asterisk denotes conformeric form): 1.4-1.6 (m, 1H), 1.6-1.9 (m, 4H), 1.9-2.0 (m, 1H), 2.75 (s, 3H)*, 2.8 (s, 3H)*, 3.0-3.2 (m, 2H)*, 3.3-3.4 (m, 2H)*, 3.4-3.6 (m, 1H)*, 3.7-3.9 (m, 1H)*, 4.4 (m, 2H), 7.2 (d, 2H), 8.2 (d, 2H), 10.6-10.8 (br s, 1H)*. 11.0-11.1 (br s, 1H)*; MS (MH+): 251.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; water; | (1) <strong>[118753-66-5]4-Amino-1-tert-butoxycarbonylpiperazine</strong> (3.00 g), 4-fluoronitrobenzene (2.54 g) and N,N-diisopropylethylamine (8.82 g) were dissolved in N-methyl-2-pyrrolidone (30 mL), and the mixture was stirred at 80C for 18 hr. The reaction mixture was added to water and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-tert-.butoxycarbonyl-4-(4-nitrophenyl)aminopiperidine (2.55 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; | Comparison Example 1 Preparing 4-nitrofluorobenzene by Reacting 4-nitrobenzene Using tetraphenylphosphonium bromide as Catalyst 157 g (1mol) of 4-nitrochlorobenzene, 400 ml of tetramethylene sulfone, and 62.7 g (1.1 mol) of potassium fluoride, but 4.19 g (0.01 mol) of tetraphenylphosphonium bromide, are employed and the procedure described in Example 1 is followed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 10h; | 2 g of para-fluoronitrobenzene was added to a solution of 20 ml of N-methylpyrrolidinone, 3.19 g of 2-ethylhexyl 3-aminopropyl ether and 2.35 g of K2CO3. The reaction medium was heated at 60 C. for 10 hours and, after it was cooled to room temperature, poured into a water+ice mixture. The resulting medium was extracted with ethyl acetate, and the organic phase was then concentrated by evaporating under vacuum. 2.73 g of N-[2-(3-ethylheptyloxy)ethyl]-4-nitro-1-aminobenzene (9) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Quinolin-4-ylmethanol (4.34 g, 0.027 mole) was taken up in tetrahydrofuran (50 mL). Potassium hydroxide (2.2 g, 0.033 mole, partially pulverized with a mortar and pestle) was added at room temperature. After 5 minutes, 4-fluoronitrobenzene (3.8 mL, 0.035 mole) was added, the mixture soon becoming a yellow slurry. More tetrahydrofuran (6 mL) was added and the reaction mixture stirred overnight. An additional amount of potassium hydroxide (0.30 g, 0.005 mole) was added and stirred for 3 more hours. The reaction mixture was stirred with water (50 mL), the solids filtered and washed with water (5 x 10 mL) to give 7.1 g of the title compound as a white solid. MS (ESI+) for C16H12N2O3 mJz 281.2 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 2h; | 2 g of 4-fluoronitrobenzene (14 mmol) was dissolved in 8 ml of N-methylpyrrolidone. One equivalent of N,N'-dimethylhexane-1,6-diamine (1.86 g) and 2.90 g of potassium carbonate were added. The reaction medium was heated at 80 C. for 2 hours. The mixture was poured onto crushed ice, and a precipitate formed. The precipitate was filtered off, washed with water and then dried. The nitro compound 3 thus obtained was then reduced with zinc. Mass: LC/MS ESI+: m/z=236 (M+1), 259 (M+1+23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A DMF solution (200 mL) of (3-hydroxypropyl)pyrrolidine (100 g) was dropwise added to a DMF (500 mL) suspension of sodium hydride (43.2 g, 60 % oil dispersion), at 0C. The reaction liquid was stirred at 0C for 10 minutes, then a DMF solution (200 mL) of 4-fluoronitrobenzene (109 g, 0.774 mol) was dropwise added to it, stirred at 0C for 1 hour and then at room temperature for 16 hours. The obtained reaction liquid was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, and dried with anhydrous magnesium sulfide, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate = 1/1 to chloroform/methanol = 9/1 to 5/1) to obtain a compound 3 (155 g, yield 83 %) as a yellow oily substance. 1HNMR (400 MHz, CDCl3, delta ppm): 1.77-1.82 (4H, m), 2.00-2.08 (2H, m), 2.50-2.54 (4H, m), 2.63 (2H, t, J=7.2 Hz), 4.12 (2H, t, J=6.4 Hz), 6.94 (2H, d, J=9.6 Hz), 8.17 (2H, d, J=9.6 z). | |
With triethylamine; In acetonitrile; for 3h;Reflux; | General procedure: To a stirred solution of 1-fluoro-4-nitrobenzene 7 (2.0 g, 14.2 mmol) in 20 mL acetonitrilewas added morpholine (1.9 g, 21.3 mmol) followed by triethylamine(4.3 g, 5.9 mL, 42.5 mmol). The mixture was stirred at reflux for 3 h.After the reaction was cooled to room temperature, it was pouredinto 80 mL water and extracted with ethyl acetate (2 x 80 mL). Thecombined organic layers were washed with brine (60 mL), driedover sodium sulfate, concentrated in vacuo, then dried under vacuumto obtain 2.7 g of 8a as yellow solid; yield: 92%; 8a was usedwithout further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | (D) To a solution of t-butyl methyl malonate (1.91 g, 11 mmol) in DMF (10 mL) was added NaH (0.849 g, 21 mmol, 60percent dispersion in oil) at 0° C. The reaction mixture was stirred for 1 h at 0° C., after which 4-fluoro-nitrobenzene (1.41 g, 10 mmol) was added. The reaction mixture was stirred for 12 h at RT, then poured into water (100 mL) and the product extracted with EtOAc (100 mL). The organic layer was washed with water (3*100 mL), dried over Na2SO4, and evaporated under vacuum. The crude product was purified by column chromatography (SiO2, hexanes:EtOAc 9:1) to provide 2-(4-nitrophenyl)-malonic acid t-butyl ester methyl ester (2 g, 68percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 12; 1-Ethyl-3-[4-(1H-pyrazolo[3,4-b]pyridin-1-yl)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 12a) 1-(4-nitrophenyl)-<strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> To a stirred solution of <strong>[271-73-8]1H-<strong>[271-73-8]pyrazolo[3,4-b]pyridine</strong></strong> (300 mg) in DMF (3.0 mL) was added sodium hydride (101 mg) (60percent in mineral oil) with ice-cooling. The mixture was stirred at room temperature for 30 min, and then 1-fluoro-4-nitrobenzene (355 mg) was added. After stirring at room temperature for 2 h, the mixture was warmed up to 50° C. The mixture was stirred at 50° C. for 12 h. Cesium carbonate (821 mg) was added and the mixture was stirred at 100° C. for 12 h, and treated with water and AcOEt. The insoluble material was filtered off. The organic layer was separated and the aqueous layer was extracted with AcOEt. The organic layer was combined, dried over MgSO4 and concentrated in vacuo. The residue was used for the next reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.36% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 6h; | Step: 20aSynthesis of 7-(4-Nitro-phenyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ajpyrazine.Procedure:K2C03 (4.4g, 0.053mol), followed by l-Fluoro-4-nitro-benzene (1.5g, 0.0177mol) was added to a solution of 3-Trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazine (3.2g, 0.0230mol) in DMF (15ml), and the flask was stirred for 6hrs at 80C. The reaction was monitored by the TLC (20% ethylacetate in hexane). From the resulting reaction mixture DMF was distilled, the residue was purified by column chromatography (using silica gel of mesh size of 60-120, 20% ethylacetate in hexane as eluant) to afford 1.2g (36.36% yield) of 7-(4-Nitro-phenyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-[l ,2,4]triazolo[4,3- ajpyrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.83g | With potassium carbonate; In acetonitrile; for 4h;Reflux; | To a solution of <strong>[827-99-6]3-trifluoromethoxy phenol</strong> (1.78g, lOmmol) and 1-fluoro-4-nitrobezene (1.41g, lOmmol) in CH3CN (4OmL) K2C03 (2.76g, 2Ommol) was added and the reaction mixture was heated to reflux for 4hrs. After filtration, the solvent was removed and the residue was washed with n-hexane (2xl5mL) and dried to afford 2.83g of nitro intermediate. To a solutionof nitro intermediate in THE (4OmL) and water (iOmL) Iron (11.20g, 200mmol) and then NH4CI (10.70g. 200mmol) were added and the reaction mixture was heated to reflux for 4hrs. After filtration, the solvent was concentrated and the residue poured into 50mL of water. The mixture was extracted with ethyl acetate (3x5OmL) and the combined organic phases were dried over MgSO4. Removal of solvent afforded 2.58g of the aniline intermediate. 269mg ofthe obtained aniline intermediate were dissolved in DCM (2OmL), Triethylamine (202mg,2mmol) and then triphosgene (118.4mg, 0.4mmol) were added and the reaction mixture was stirred at room temperature for 4hrs. Triethylamine (202mg, 2mmol) and acetohydrazide (74mg, lmmol) were added to the above solution and the reaction mixture was stirred at room temperature overnight. Removal of solvent afforded crude material, which was purifiedby flash chromatography on silica gel using dichloromethane/methanol 200:1 as eluents to give 288mg of urea intermediate. It was dissolved in an aqueous 2M solution of NaOH (l5mL) and the reaction mixture was heated to reflux for l2hrs. The mixture was neutralized with aqueous 6N HCI and extracted with DCM (3x5OmL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude compound. which was purified byflash chromatography on silica gel using dichloromethane/methanol 100:1 as eluents to afford 35mg of title compound as white solid.MS_i (ESI) m/z calcd for Ci6Hi2F3N3O3 351.28, found 352.i(MH ).1HNMR (400 MHz, DMSO-d6): 5 ppm li.60 (1H, s), 7.58-7.45 (3H, m), 7.22-7.08 (5H, m), 2.06 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium hydrogencarbonate; In ethanol; water; for 16h;Reflux; | A mixture of 1-fluoro-4-nitrobenzene (1.00 g, 7.09 mmol),N-methyl-c-aminobutyric acid hydrochloride (1.20 g, 7.80 mmol)and NaHCO3 (1.49 g, 17.73 mmol) in EtOH/H2O (1:1, 100 mL) washeated at reflux for 16 h. The reaction mixture was allowed to coolto room temperature and the ethanol was evaporated. The remainingsolution was acidified to pH 1?2 by the addition of 2 MaqueousHCl solution. The mixture was extracted twice with EtOAc, thecombined organic extracts were washed with H2O and then brine,dried (MgSO4) and evaporated giving compound 38 (1.04 g, 62percent) asa yellow solid, mp 139?141 C. LRMS (ESI) for C11H15N2O4.Calculated mass of molecular ion [M+H]+ 239.25. Measured mass:239.05; IR mmax cm1 3000, 1686, 1577, 1477, 1226; 1H NMR(270 MHz; d6-DMSO) dH 12.17 (1H, s, br, OH), 8.04 (2H, d,J = 9.14 Hz, Ar-H), 6.80 (2H, d, J = 9.7 Hz, Ar-H), 3.49 (2H, t,J = 7.4 Hz, CH2), 3.05 (3H, s, N-CH3), 2.29 (2H, t, J = 7.4 Hz, CH2),1.74 (2H, quintet, J = 7.4 Hz, CH2); 13C NMR (101 MHz; d6-DMSO)dC 174.7 (CO), 154.0 (Ar-C), 135.9 (Ar-C), 126.4 (2 Ar-C), 111.1(2 Ar-C), 51.4 (CH2), 38.8 (CH3), 31.1 (CH2), 22.2 (CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With potassium carbonate; In N,N-dimethyl-formamide; for 24.0h;Inert atmosphere; Reflux; | Under nitrogen <strong>[626-13-1]m,m'-di-tolylamine</strong> 1.97g (10mmol) and 1-fluoro-4-nitrobenzene, 1.41g (10mmol) dissolved in 15ml of DMF and then 0.83g K2CO3 (6mmol) was added for 24 hours under reflux wasWhen the reaction is complete, cool the temperature of the reaction to room temperature, the solid was dried generated by the addition of 50ml H2O and filtered The dried product Hex:. MC = 2: 1 in the column to give the intermediate G 1.94g (61%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | As illustrated in Fig. S2, a mixture of 1-fluoro-4-nitrobenzene (1.1 mL, 10.0 mmol), <strong>[141483-15-0]2-fluoro-5-(trifluoromethyl)phenol</strong> (3.60 g, 20.0 mmol) and potassium carbonate (2.76 g, 20.0 mmol) in DMF (10 mL) was stirred at 100 C for 4 h. Then diethyl ether was added to the reaction mixture, whereafter the solution was washed with 2 M NaOH (2 x 30 mL), water (30 mL), brine (30 mL), dried over Na2SO4, and filtered. Finally, the resulted organic layer was evaporated under reduced pressure to give a crude mixture which was used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
330 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | A mixture containing 1-fluoro-4-nitrobenzene (282 mg), <strong>[7343-34-2]3,5-dimethyl-1H-1,2,4-triazole</strong> (194 mg), potassium carbonate (552 mg)and DMF (6 mL) was stirred at 80 C. overnight. The reaction mixture was cooled to room temperature and ethyl acetate was then added thereto, and washing with water was performed. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and thereby 3,5-dimethyl-1-(4-nitrophenyl)-1H-1,2,4-triazole (330 mg) was obtained. |
Tags: 350-46-9 synthesis path| 350-46-9 SDS| 350-46-9 COA| 350-46-9 purity| 350-46-9 application| 350-46-9 NMR| 350-46-9 COA| 350-46-9 structure
A812339 [1958100-79-2]
1-Fluoro-4-nitrobenzene-1,2,3,4,5,6-13C6
Reason: Stable Isotope
A123574 [364-75-0]
1-Fluoro-4-iodo-2-nitrobenzene
Similarity: 0.73
A123574 [364-75-0]
1-Fluoro-4-iodo-2-nitrobenzene
Similarity: 0.73
A123574 [364-75-0]
1-Fluoro-4-iodo-2-nitrobenzene
Similarity: 0.73
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